The transdermal route of parenteral drug delivery provides many advantages. Unfortunately, however, many drugs which are candidates for transdermal delivery have a tendency to cause skin irritation to human patients, particular when they are maintained in contact with the skin under occlusion for sustained periods of time. These irritating drugs can cause undesirable skin reactions, such as itching and erythema. Therefore, despite the development of the transdermal drug delivery art, there remains a continuing need for an improved method of overcoming irritation caused by transdermal delivery of an irritating drug.
Skin irritation can be caused by a variety of factors including, but not limited to, physical factors (e.g., chafing or occluding the skin in an airtight manner), exposure to certain chemicals, exposure to pH outside the normal pH range of the skin or mucosa, and bacterial overgrowth. Generally, tissue irritation is the manifested result of damage or toxicity to cells in the skin or mucosa caused by their response to a cytotoxic (i.e., irritating) agent.
Investigators have found that amphiphilic weak bases tend to accumulate extensively in body tissues. While this is due in part to the interaction such compounds with membranes, it is also due to a large extent to the fact that weak bases accumulate in lysosomes as a result of the low intralysosomal pH (MacIntyre et al., Biopharm. & Drug Disposition, 9:513-526 (1988); Hollemans et al., Biochim. Biophys. Acta, 643:140-151 (1981)).
Lysosomes are small membrane-enclosed organelles which are found within almost all animal cells. Under normal conditions, lysosomes have an internal pH in the range of 4.5 to 5. In contrast, the physiological pH outside the cell is about 7.0. This difference results in extensive accumulation within the lysosome of weak bases. The weak bases can permeate the cell and the lysosomal membranes in their uncharged molecular form. However, the low internal pH of lysosomes favors protonation of the weak base molecules; once they are charged, the molecules are relatively membrane-impermeable and less able to pass back through the membrane.
Several important drugs are weak bases and have been shown to accumulate in lysosomes. These drugs include, for example, the betaadrenergic antagonist propranolol (Cramb, Biochem. Pharmacol., 35:1365-1372 (1986)) and the antimalarial drug chloroquine (Reijngoud et al., FEBS Letters, 64:231-235 (1976)). The accumulation of these weak bases can be inhibited by competition using other amphiphilic amines by virtue of the fact that weak bases raise the pH in the lysosome (Maxfield, J. Cell Biol., 95:676-681 (1982); Ohkuma et al., Proc. Natl. Acad. Sci. USA, 75:3327-3331 (1978)).
Other compounds, the ionophores, have also been shown to raise the pH in lysosomes (Maxfield, ibid.; Ohkuma et al., ibid.). The ionophores incorporate in the lysosomal membranes and facilitate the exchange of ions, thereby destroying the normally-existing pH gradient (Pressman, "Alkali Metal Chelators--The Ionophores", in, Eichhorn, ed., Inorganic Biochemistry, Vol. 1, pp. 218-221, Elsevier Scientific Publishing Co., N.Y., 1973).